The objective of this research project is to develop [18F]radiotracers that can be used to image brain and systemic tumors in vivo based upon amino acid transport with the imaging technique Positron Emission Tomography (PET). Our approach will focus on the development of [18F]cyclobutyl and [18F]branched nonmetabolized amino acids that move across tumor capillaries by carrier-mediated facilitated transport involving either the "L" large-neutral amino acid or "A" alanine amino acid transport systems. Preliminary evaluation of amino acids labeled with positron emitters and which are substrates for the "L" and "A" transport systems have shown excellent potential in clinical oncology for tumor imaging in patients with brain and systemic tumors. The development of this class of radiotracers with optimal imaging properties remains an active area of investigation. Our choice of cyclobutyl and branched nonmetabolized amino acids as suitable radiopharmaceuticals for imaging tumors stems from our preliminary in vitro studies in rat 9L gliosarcoma cells demonstrating that fluorine containing cyclobutyl analogs show high and selective uptake by the type "L" transport system while the fluorine containing (R,S) alpha-amino isobutyric acid (AIB) analogs show high and selective uptake by the type "A" transport system. Secondly, our preliminary in vivo studies in rats with intracranial 9L rat tumor implants displayed high 6:1 tumor to brain ratios for [18F]cyclobutyl nonmetabolized amino acids and even higher 37-100:1 tumor to brain ratios for the [18F]AIB nonmetabolized amino acids. Finally, low uptake of the cyclobutyl analogs in the kidney, lungs and muscle in rats and low uptake of the AIB analogs in lungs and muscle strongly support our proposed studies to evaluate [18F]cyclobutyl/AIB analogs in tumor bearing mice implanted with human derived tumors in order to determine their potential as imaging agents for systemic solid tumors. The Specific Aims of this proposal are: 1) to synthesize nonmetabolized amino acids that have high uptake in human derived tumors and high selectivity for either the "L" large-neutral amino acid or "A" alanine amino acid transport systems; 2) to synthesize the precursors for 18F-labeling and to prepare the corresponding [18F]amino acids for the in vitro and in vivo evaluation studies; 3) to determine the uptake and transport mechanism of the [18F]amino acids in different tumor cell lines with different malignant phenotypes; 4) to determine the biodistribution and metabolic stability of the most promising "L"-type and "A"-type selective amino acids in tumor-bearing mice with human (DU145) prostate tumors, (SKOV3) ovarian tumors, (A549) lung tumors, (EB) colon tumors, (HTB-46) renal tumors, and (MDA MB468) breast tumors. Our hypotheses include: 1) [18F]cyclobutyl and [18F]AIB analogs will demonstrate high selectivity for the "L" and "A" transport systems, respectively in a number of common human tumors and high tumor to normal tissue ratios in vivo; 2) [18F]cyclobutyl and [18F]AIB analogs will provide clinically useful and important information, especially in brain, kidney, and prostate tumors, which cannot be obtained using other currently available imaging modalities including PET imaging with 2-[18F]FDG) or [11C]-methyl]- methionine or by contrast enhanced computed tomography (CT) and magnetic resonance imaging (MRI); 3) [18F]cyclobutyl and [18F]AIB analogs will provide substantial logistical and economic benefits for tumor imaging in a nuclear medicine clinic as compared to [11C]amino acids, due to the [18F] half-life (t1/2=110 min), a large number of doses can be prepared from a single batch production ,the alternative [11C] (t1/2=20 min,) can only provide relatively few doses from each batch production of [11C]amino acid.